7-12337012-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001135924.3(VWDE):c.4534T>C(p.Trp1512Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: VWDE NM_001135924.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.65

Genes affected

VWDE (HGNC:21897): (von Willebrand factor D and EGF domains) Predicted to enable signaling receptor binding activity. Predicted to be involved in anatomical structure development. Predicted to be active in cell surface and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWDE	NM_001135924.3	c.4534T>C	p.Trp1512Arg	missense_variant	26/29	ENST00000275358.8
VWDE	NM_001346972.2	c.4189T>C	p.Trp1397Arg	missense_variant	24/27
VWDE	NM_001346973.2	c.3724T>C	p.Trp1242Arg	missense_variant	24/27
VWDE	NR_144534.2	n.5356T>C		non_coding_transcript_exon_variant	27/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWDE	ENST00000275358.8	c.4534T>C	p.Trp1512Arg	missense_variant	26/29	5	NM_001135924.3	P1
VWDE	ENST00000452576.6	c.*1298T>C		3_prime_UTR_variant, NMD_transcript_variant	27/30	1
VWDE	ENST00000521169.5	c.*2912T>C		3_prime_UTR_variant, NMD_transcript_variant	23/26	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000641 AC: 1 AN: 156114 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399154 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The c.4534T>C (p.W1512R) alteration is located in exon 26 (coding exon 26) of the VWDE gene. This alteration results from a T to C substitution at nucleotide position 4534, causing the tryptophan (W) at amino acid position 1512 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.69	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.82
MutPred		0.66		Gain of methylation at W1512 (P = 0.0558);
MVP		0.50
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1351969166; hg19: chr7-12376638;